Brand Names: U.S.

Pharmacologic Category

Pharmacology

Potent inhibitor of norepinephrine and serotonin reuptake (3:1). Milnacipran has no significant activity for serotonergic, alpha- and beta-adrenergic, muscarinic, histaminergic, dopaminergic, opiate, benzodiazepine, and GABA receptors. It does not possess MAO-inhibitory activity.

Absorption

Well absorbed

Distribution

IV: Vd: ~400 L

Metabolism

Hepatic to inactive metabolites

Excretion

Urine (55% as unchanged drug)

Time to Peak

Plasma: Oral: 2-4 hours

Half-Life Elimination

6-8 hours

Protein Binding

13%

Special Populations: Renal Function Impairment

The AUC increased by 16%, 52%, and 199%, and terminal half-life increased by 38%, 41%, and 122% in patients with mild, moderate, and severe renal impairment, respectively.

Special Populations: Hepatic Function Impairment

AUC and half-life are similar in healthy subjects and subjects with mild and moderate hepatic impairment. In subjects with severe hepatic impairment, the AUC and half-life are increased 31% and 55%, respectively, compared with healthy subjects.

Special Populations: Elderly

Because of age-related decreases in renal function, Cmax and AUC are ~30% higher in those >65 years of age compared with younger subjects.

Special Populations: Gender

Cmax and AUC of milnacipran were ~20% higher in women compared with men.

Use: Labeled Indications

Fibromyalgia: Management of fibromyalgia

Contraindications

Use of MAOIs intended to treat psychiatric disorders (concurrently or within 5 days of discontinuing milnacipran, or within 2 weeks of discontinuing the MAOI); initiation of milnacipran in a patient receiving linezolid or methylene blue IV

Dosing: Adult

Fibromyalgia: Oral: 50 mg twice daily.

Titration schedule: 12.5 mg once on day 1, then 12.5 mg twice daily on days 2-3, 25 mg twice daily on days 4-7, then 50 mg twice daily thereafter. Dose may be increased to 100 mg twice daily, based on individual response. Doses >200 mg daily have not been studied.

Discontinuation of therapy: Upon discontinuation of antidepressant therapy, gradually taper the dose to minimize the incidence of withdrawal symptoms and allow for the detection of re-emerging symptoms. Evidence supporting ideal taper rates is limited. APA and NICE guidelines suggest tapering therapy over at least several weeks with consideration to the half-life of the antidepressant; antidepressants with a shorter half-life may need to be tapered more conservatively. In addition for long-term treated patients, WFSBP guidelines recommend tapering over 4-6 months. If intolerable withdrawal symptoms occur following a dose reduction, consider resuming the previously prescribed dose and/or decrease dose at a more gradual rate (APA 2010; Bauer 2002; Haddad 2001; NCCMH 2010; Schatzberg 2006; Shelton 2001; Warner 2006).

MAO inhibitor recommendations:

Switching to or from an MAO inhibitor intended to treat psychiatric disorders:

Allow ≥14 days to elapse between discontinuing an MAO inhibitor intended to treat psychiatric disorders and initiation of milnacipran.

Allow ≥ 5 days to elapse between discontinuing milnacipran and initiation of MAO inhibitor intended to treat psychiatric disorders.

Use with other MAO inhibitors (linezolid or IV methylene blue):

Do not initiate milnacipran in patients receiving linezolid or IV methylene blue; consider other interventions for psychiatric condition.

If urgent treatment with linezolid or IV methylene blue is required in a patient already receiving milnacipran and potential benefits outweigh potential risks, discontinue milnacipran promptly and administer linezolid or IV methylene blue. Monitor for serotonin syndrome for 5 days or until 24 hours after the last dose of linezolid or IV methylene blue, whichever comes first. May resume milnacipran 24 hours after the last dose of linezolid or IV methylene blue.

Apixaban: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Apixaban. Specifically, the risk for bleeding may be increased. Management: Carefully consider risks and benefits of this combination and monitor closely. Monitor therapy

Cephalothin: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Cephalothin. Specifically, the risk for bleeding may be increased. Monitor therapy

ClomiPRAMINE: May enhance the adverse/toxic effect of Milnacipran. Specifically, the incidence of euphoria and postural hypotension were higher in patients changing from clomipramine to milnacipran. ClomiPRAMINE may enhance the serotonergic effect of Milnacipran. This could result in serotonin syndrome. Management: Coadminister with caution. Monitor more closely for euphoria, postural hypotension, serotonin toxicity/serotonin syndrome, and other adverse events when switching from clomipramine to milnacipran or if these drugs are to be used in combination. Consider therapy modification

Collagenase (Systemic): Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased. Monitor therapy

Dabigatran Etexilate: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Dabigatran Etexilate. Agents with Antiplatelet Properties may increase the serum concentration of Dabigatran Etexilate. This mechanism applies specifically to clopidogrel. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Monitor therapy

Dasatinib: May enhance the anticoagulant effect of Agents with Antiplatelet Properties. Monitor therapy

Deoxycholic Acid: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased. Monitor therapy

Digoxin: Milnacipran may enhance the adverse/toxic effect of Digoxin. The risk of postural hypotension and tachycardia may be increased, particularly with IV digoxin. Management: Avoid concurrent use of intravenous (IV) digoxin in patients receiving milnacipran. Use caution when using oral digoxin and milnacipran together, monitoring closely for possible postural hypotension and tachycardia. Consider therapy modification

Edoxaban: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Edoxaban. Specifically, the risk of bleeding may be increased. Monitor therapy

Glucosamine: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Ibritumomab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Ibritumomab. Both agents may contribute to impaired platelet function and an increased risk of bleeding. Monitor therapy

Ibrutinib: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Monitor therapy

Opioid Analgesics: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Pentosan Polysulfate Sodium: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Specifically, the risk of bleeding may be increased by concurrent use of these agents. Monitor therapy

Pentoxifylline: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Tipranavir: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Tositumomab and Iodine I 131 Tositumomab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Tositumomab and Iodine I 131 Tositumomab. Specifically, the risk of bleeding-related adverse events may be increased. Monitor therapy

TraMADol: Serotonin Modulators may enhance the adverse/toxic effect of TraMADol. The risk of seizures may be increased. TraMADol may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

ALERT: U.S. Boxed Warning

Suicidality and antidepressant drugs:

Milnacipran is a selective serotonin-norepinephrine reuptake inhibitor (SNRI), similar to some drugs used for the treatment of depression and other psychiatric disorders. Antidepressants increased the risk, compared with placebo, of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of such drugs in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared with placebo in adults older than 24 years; there was a reduction in risk with antidepressants compared with placebo in adults 65 years and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on milnacipran should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Milnacipran is not approved for use in the treatment of MDD. Milnacipran is not approved for use in pediatric patients.

Warnings/Precautions

Major psychiatric warnings:

• Suicidal thinking/behavior: [US Boxed Warning]: Milnacipran is a serotonin/norepinephrine reuptake inhibitor (SNRI) similar to SNRIs used to treat depression and other psychiatric disorders. Antidepressants increase the risk of suicidal thinking and behavior in children, adolescents, and young adults (18-24 years of age) with major depressive disorder (MDD) and other psychiatric disorders; consider risk prior to prescribing. Short-term studies did not show an increased risk in patients >24 years of age and showed a decreased risk in patients ≥65 years. Closely monitor for clinical worsening, suicidality, or unusual changes in behavior; the patient’s family or caregiver should be instructed to closely observe the patient and communicate condition with health care provider. A medication guide concerning the use of antidepressants in children and teenagers should be dispensed with each prescription. Milnacipran is not FDA-approved for the treatment of major depressive disorder or for use in children.

• Suicide risk: Suicide risks should be monitored in patients treated with SNRIs regardless of the indication. The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Patients treated with antidepressants should be observed for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Worsening depression and severe abrupt suicidality that are not part of the presenting symptoms may require discontinuation or modification of drug therapy. Use caution in high-risk patients during initiation of therapy.

• Prescriptions should be written for the smallest quantity consistent with good patient care. The patient's family or caregiver should be alerted to monitor patients for the emergence of suicidality and associated behaviors such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania; patients should be instructed to notify their healthcare provider if any of these symptoms or worsening depression or psychosis occur.

Concerns related to adverse effects:

• Bleeding risk: May impair platelet aggregation resulting in increased risk of bleeding events, particularly if used concomitantly with aspirin or NSAIDs due to ulcerogenic potential. Data are inconclusive regarding extent of bleeding risk of SNRIs in combination with warfarin or other anticoagulants. Bleeding related to SNRI use has been reported to range from relatively minor bruising and epistaxis to life-threatening hemorrhage.

• Cardiovascular effects: May increase blood pressure and heart rate. Pre-existing cardiovascular disease (including hypertension and tachyarrhythmias) should be treated prior to initiating therapy. Blood pressure and heart rate should be evaluated prior to initiating therapy and periodically thereafter; consider dose reduction or gradual discontinuation of therapy in individuals with sustained hypertension or tachycardia during therapy. Use with caution in patients with pre-existing hypertension, tachyarrhythmias (eg, atrial fibrillation), or other cardiovascular disease; and with concomitant medications known to increase blood pressure or heart rate.

• Fractures: Bone fractures have been associated with antidepressant treatment. Consider the possibility of a fragility fracture if an antidepressant-treated patient presents with unexplained bone pain, point tenderness, swelling, or bruising (Rabenda 2013; Rizzoli 2012).

• Hepatotoxicity: Avoid use in patients with substantial ethanol intake, evidence of chronic liver disease or hepatic impairment. Cases of increased liver enzymes and severe liver injury (including fulminant hepatitis) have been reported. Discontinue therapy with the presentation of jaundice or other signs of hepatic dysfunction and do not reinitiate therapy unless another source or cause is identified.

• Ocular effects: May cause mild pupillary dilation which in susceptible individuals can lead to an episode of narrow-angle glaucoma. Consider evaluating patients who have not had an iridectomy for narrow-angle glaucoma risk factors.

• SIADH and hyponatremia: SSRIs and SNRIs have been associated with the development of SIADH; hyponatremia has been reported rarely (including severe cases with serum sodium <110 mmol/L), predominately in the elderly. Volume depletion and/or concurrent use of diuretics likely increases risk.

• Urinary hesitancy: May cause increased urinary resistance; advise patient to report symptoms of urinary hesitation/difficulty. Use caution in patients with a history of dysuria, especially males with prostatic hypertrophy, prostatitis, or other lower urinary tract disorders.

Disease-related concerns:

• Mania/hypomania: Patients with major depressive disorder were excluded from clinical trials evaluating milnacipran for fibromyalgia; however, mania has been reported in patients with mood disorders taking similar medications. May worsen psychosis in some patients or precipitate a shift to mania or hypomania in patients with bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. Patients presenting with depressive symptoms should be screened for bipolar disorder. Milnacipran is not FDA approved for the treatment of bipolar disorder.

• Seizure disorders: Use caution with a previous seizure disorder or condition predisposing to seizures such as brain damage or alcoholism.

Concurrent drug therapy issues:

• MAO inhibitors: Potential for severe reaction when used with MAO inhibitors; autonomic instability, coma, death, delirium, diaphoresis, hyperthermia, mental status changes/agitation, muscular rigidity, myoclonus, neuroleptic malignant syndrome features, and seizures may occur. Concurrent use is contraindicated. Do not use milnacipran in combination with an MAO inhibitor or within 14 days of discontinuing an MAO inhibitor; do not start an MAO inhibitor until ≥5 days after discontinuing milnacipran.

Monitoring Parameters

Blood pressure and heart rate should be regularly monitored; renal function should be monitored for dosing purposes; mental status for suicidal ideation (especially at the beginning of therapy or when doses are increased or decreased); intraocular pressure should be monitored in those with baseline elevations or a history of glaucoma

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies. Nonteratogenic effects in the newborn following SSRI/SNRI exposure late in the third trimester include respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hyper- or hypotonia, hyper-reflexia, jitteriness, irritability, constant crying, and tremor. Symptoms may be due to the toxicity of the SNRIs/SSRIs or a discontinuation syndrome and may be consistent with serotonin syndrome associated with SSRI treatment. The long-term effects of in utero SNRI/SSRI exposure on infant development and behavior are not known.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.